Lithium

Pharmacokinetics of Lithium

Absorption Lithium is rapidly absorbed from the GI tract, with Tmax= 1-3 hours (adults). With extended-release tablets (Lithmax SR), absorption is delayed, with Tmax=4-12 hours (adults). Food or antacids do not appear to influence absorption.
Distribution Lithium is not protein bound, and distributes freely throughout body water, both intra- and extracellularly
Metabolism Lithium is not metabolized, rather, it is excreted almost entirely by the kidneys (95%).
Elimination Lithium is excreted almost exclusively excreted by the kidneys; most lithium is reabsorbed at the proximal convoluted tubules via sodium channels.
Half-life 18-36 hours

Lithium: Cytochrome P450 Metabolism

Substrate of (Metabolized by) Not applicable
Induces -
Inhibits -
  • Since sodium is so pervasive in the human body and lithium can also alter these processes, it has been very difficult to identify the key mechanism of action of lithium in regulating mood.
    • For example, there is some evidence that people with bipolar illness have higher intracellular concentrations of sodium and calcium than controls, and that lithium can reduce these.
  • Lithium is hypothesized to modulate dopaminergic, glutamatergic and gabaergic neurotransmission.[1] Lithium alters sodium transport across the cell membranes of nerve and muscle cells. There are multiple proposed mechanisms for lithium in its role in treatment of mania and bipolar disorder, including:
    • Inhibition of inositol monophosphatase intracellular signaling
    • Altering metabolism of neurotransmitters including catecholamines and serotonin
    • Effects neural plasticity through effects on glycogen synthetase kinase-3β , cyclic AMP- dependent kinase, protein kinase C
    • Increasing cytoprotective proteins
    • Activating signaling cascade used by endogenous growth factors
    • Potentially inducing neurogenesis at synaptic sites.
  • Subsequent actions by lithium include:
    • Increasing synthesis of serotonin by increasing tryptophan reuptake in synaptic terminals
    • Downregulation of 5-HT1A, 5-HT1B, 5-HT2 receptors
    • Increasing rate of synthesis of norepinephrine
    • During manic episodes, lithium is thought to reduce the excretion of norepinephrine
    • During manic episodes, lithium is thought to increase excretion of norepinephrine metabolites

Most risk factors for developing lithium toxicity involve changes in sodium levels or the way the patient's body handles sodium. For example low salt diets, dehydration, drug-drug interactions (see below) and illnesses like Addison’s disease can lead to toxicity. Patients should be well-informed of these risk factors when starting treatment.

Toxic Lithium Levels

Level (mmol/L) Symptoms
>1.5 • GI symptoms (anorexia, nausea and diarrhea)
• CNS symptoms (muscle weakness, drowsiness, ataxia, course tremor and muscle twitching).
>2.0 • Blurred vision, confusion, slurred speech, unsteady gait.
• Increased disorientation and seizures usually occur, which can progress to coma, and ultimately death.
• Osmotic or alkaline diuresis can be used (not thiazide or loop diuretics, which would worsen symptoms!)
>3.0 • Severe toxicity, coma, cardiovascular collapse, death.
• Peritoneal or hemodialysis is often used for emergency management.
    • Lithium is effective in the treatment of moderate to severe mania (NNT = 6), and for prophylaxis of bipolar affective disorder (reduces both the number and the severity of relapses, NNT = 10-14).[2]
    • Lithium is more effective at preventing manic than depressive relapse. Lithium also offers some protection against antidepressant‐induced hypomania.
    • It is generally clinically appropriate to initiate prophylactic treatment after a single manic episode that was associated with significant risk and adverse consequences, or in bipolar I illness, two or more acute episodes.
  • Major depressive disorder, most commonly as an adjunctive medication

Dosing for Lithium

Starting • Outpatient: 300 mg PO daily for the first week
• Inpatient: 600 mg PO daily for the first week and generally titrated more aggressively
Titration Increments of 300 to 600 mg each week during the titration phase
Maximum Typically does not exceed 2400 mg per day (though the lithium level is most important)
Taper See below

Lithium Levels

Level (mmol/L)
Maintenance/prophylaxis 0.6 to 1.0
Acute bipolar mania/depression (<65 years) 0.8 to 1.2*
Acute bipolar mania/depression (>65 years) 0.4 to 0.8
Toxic levels > 1.5 mmol/L
  • It is the lithium plasma level (not the lithium dose) that is clinically significant.
  • Keep in mind that rapid increases will lead to more GI side effects.
  • Children and adolescents may require higher plasma levels than adults due to differences in drug distribution and pharmacokinetics. The optimal plasma level ranges for lithium used unipolar depression are less clear, and typically do not need to reach the levels used in bipolar disorder.
  • Once daily dosing can reduce the severity of side effects of lithium.[3]
  • Dosing it at night can also be helpful because lithium can be sedating for some patients. Patients should be reminded to drink more water to ensure hydration, and to also reduce their salt intake.

Calculating the target dose

To calculate how much to increase a dose by, take the current dose the patient is at, and divide it over the current lithium level. For example, if your patient is taking 600mg per day, and their most recent lithium level is 0.5 (i.e. - subtherapeutic), and you want to reach a level of 0.8, you would do the following calculation:


960mg would be the next dose to give to your patient to reach the target dose of 0.8. You would need to wait another 5 half-lives before measuring the trough levels again.
  • Lithium comes in oral and liquid formulation.

What Time Should the Bloodwork Be Done?

Lithium is rapidly absorbed from the gastrointestinal tract but has a long distribution phase. Plasma lithium levels should be taken 10–14 hours (ideally 12 hours) after the last dose. Therefore, your patients should not be taking lithium the morning of the bloodwork! They can take their dose again after their blood work.

Lithium Monitoring

Stage of treatment Everyone High Risk/Geriatric
Pre-treatment Cr (eGFR), BUN, TSH, total calcium, albumin, weight, height, blood pressure ECG (cardiovascular risks or dysfunction), fasting glucose, lipid panel
Starting • Plasma lithium level 7 days after starting treatment (you are measuring the trough level, i.e. - 12 hours after last dose)
• Measure plasma lithium after another 7 days, and titrate dose as needed.
• This q1-2 weekly monitoring should continue until you have 2 consecutive levels within the therapeutic range (0.8 to 1.2) for the same dosage
Start with a lower dose of lithium, with similar monitoring
Ongoing • Plasma lithium level, electrolytes, Cr (eGFR), TSH, BUN, q6-12 months.
• Serum calcium, albumin, q1 year
• Parathyroid hormone levels should be measured in patients with elevated calcium levels
Elderly, those with drug-drug interactions, existing renal impairment, or other illnesses should be monitored more closely.
Stopping Dose needs to be reduced slowly over the course of 1 month. Reductions in plasma level should not be > 0.2mmol/L each time you reduce the dose.

Never Discontinue Lithium Abruptly!

Discontinuing lithium abruptly or in less than 2 weeks, rather than tapering (> 2 weeks) doubles the risk of a recurrent mood episode in 1 year; and the risk increases by 20 times in 3 years. At least 1 month should be spent tapering off lithium.[4] Abrupt discontinuation of lithium and may actually exceed that of the risk of the untreated disorder.[5][6][7] The reason for this “rebound effect” remains (unfortunately) a poorly understood mechanism.
  • Intermittent treatment with lithium may worsen the natural course of bipolar illness. A much greater than expected incidence of manic relapse is seen in the first few months after discontinuing lithium,[8] even in patients who have been symptom free for as long as 5 years.[9]
  • Some recommendations have been made that lithium treatment should not be started unless there is a clear intention to continue it for at least 3 years.[10]
    • This advice has obvious implications for initiating lithium treatment against a patient’s will (or in a patient known to be non‐adherent with medication) during a period of acute illness.
  • Sodium balance (i.e. - salt intake) can have an impact on lithium levels. When there is sodium depletion (i.e. - hyponatremia or low sodium intake), lithium undergoes higher reabsorption, resulting in higher serum levels. Conversely, when there is high sodium intake, there is decreased lithium reabsorption, resulting in lower serum levels.
  • Lithium may have neuroprotective effects, possibly mediated through its effects on N‐methyl‐D‐aspartate (NMDA) pathways.[11] It is important to note that the literature suggesting these neuroprotective effects are based on in vitro and animal studies, and not in humans.[12]
  • Lithium is only one of two psychotropics (the other is clozapine) that has been clinically shown to reduce the risk of suicide.[13]
    • The finding of anti-suicidal effects is much stronger for lithium than clozapine.[14][15]
  • The mechanism of this is still under investigation, but theories focus largely on its effects on neurotransmitters. The most common hypothesis is that lithium leads to a decrease in impulsivity and aggression via several influences within the nerve cell.[16]
  • Lithium should not be used during first trimester of pregnancy, due to increased risk for Ebstein's anomaly (cardiac malformation)
    • Although traditionally considered an absolute contraindication, there is some argument from certain clinicians that the risks and benefits should be discussed with the individual patient (e.g. - high risk for relapse or severe deterioration when off lithium).[17]
  • Severe renal impairment
  • Cardiovascular disease with arrythmias (can cause reversible T-wave changes, or unmask Brugada syndrome)
  • Addison's disease
  • Mild renal disease

Common Drug-Drug Interactions

Adapted from: Taylor, D. M. et al. (2018). The Maudsley prescribing guidelines in psychiatry. John Wiley and Sons.
Drug Examples Interaction
ACE Inhibitors Captopril, cilazapril enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril Reduces thirst which can lead to mild dehydration. Increases renal sodium loss leading to increased sodium re‐absorption by the kidney, resulting in an increase in lithium plasma levels. In the elderly, ACE inhibitors increase seven‐fold the risk of hospitalisation due to lithium toxicity. ACE inhibitors can also precipitate renal failure so, if co‐prescribed with lithium, more frequent monitoring of e‐GFR and plasma lithium is required.
Angiotensin II Receptor Antagonists (ARBs) Candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan Similar drug-drug interactions as with ACE inhibitors.
Thiazide Diuretics Bumetanide, furosemide and torasemide Reduces renal clearance of lithium. Thiazide diuretics have a much larger effect compared to loop diuretics. Lithium levels usually rise within 10 days of a thiazide diuretic being prescribed; the magnitude of the rise is unpredictable and can vary from an increase of 25% to 400%. Although there are case reports of lithium toxicity induced by loop diuretics, many patients receive this combination of drugs without apparent problems.
NSAIDs / COX-2 Inhibitors Aceclofenac, acemetacin, celecoxib, dexibuprofen, dexketofrofen, diclofenac, diflunisal, etodolac, etoricoxib, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, lumiracoxib, mefenamic acid, meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam and tiaprofenic acid NSAIDs inhibit the synthesis of renal prostaglandins, reducing renal blood flow, which increases renal re‐absorption of sodium and therefore lithium. The magnitude of the rise is unpredictable for any given patient; case reports vary from increases of around 10% to over 400%.
  • Side effects with lithium are dose-related. Therefore, knowing the plasma level of lithium allows you to gauge the degree of side effects that a patient might encounter. If a patient isn't experiencing any side effects at all (even minor ones), it should already tell you that they are likely on a very subtherapeutic dose of lithium.
  • The most common side effects of lithium include: metallic taste in the mouth, gastro‐intestinal upset such as diarrhea, fine tremors, polyuria and polydipsia (polyuria may occur more frequently with BID dosing), ankle edema, and weight gain.

Mnemonic

The mnemonic LMNOP can be used to remember important side effects and adverse events related to lithium:
  • L - Lithium
  • M - Movement (tremor)
  • N - Nephrology (kidney injury) and nephrogenic diabetes insipidus (thirst and urination)
  • O - HypOthyroidism
  • P - Pregnancy (Ebstein's anomaly)
  • Psoriasis, acne, alopecia can also occur (hair often regrows with or without stopping lithium).
  • Nephrogenic diabetes insipidus (NDI) is characterized by intense thirst and polyuria with inability to concentrate urine due to a reduction of ADH (antidiuretic hormone, also known as vasopressin). Chronic lithium use can cause ADH resistance in the kidneys, leading to decreased urinary concentrating capacity. NDI is usually reversible in the short to medium term but may be irreversible after long‐term treatment with lithium (i.e. - over 15 years).
  • Lithium levels that are >0.8 mmol/L are associated with a higher risk of nephrotoxicity. NDI can be diagnosed with a water restriction test, and considered positive when there is no change in urine osmolality despite restriction.
  • Management includes discontinuing lithium, reducing the daily dosage, or reducing the dosing schedule. Diuretics can also be used to treat NDI, but requires close monitoring of lithium and potassium levels.[18]
  • Long-term lithium use increases the risk of hypothyroidism. In middle‐aged women, the risk may be up to 20%, while up to 30% develop asymptomatic elevated TSH. Lithium-related hypothyroidism can be easily treated with levothyroxine.
  • Some clinicians suggest testing for thyroid autoantibodies in middle-aged women before starting lithium (to better estimate the risk of hypothyroidism) and for monitoring more frequently in the first year of treatment.[19]
  • Lithium increases the risk of hypercalcemia and hyperparathyroidism (prevalence of ~5%).[20] Up to 10% of patients on long-term lithium treatment develop hypercalcaemia and hyperparathyroidism, and this is even higher in the geriatric population.[21]
  • These two conditions are frequently under-diagnosed in psychiatric practice and there are recommendations that calcium levels should be monitored in patients on long‐term treatment.[22] Sequelae of long-term chronic hypercalcemia includes renal stones, osteoporosis, dyspepsia, hypertension and renal impairment.
  • Symptoms of hypercalcemia (and consequently hyperparathyroidism) can also mimic as psychiatric disorders, with disturbances of mood, energy, and cognition.
  • Lithium can cause leukocytosis, neutrophilia, and increased platelet counts.[23]
  • Lithium can cause changes on ECG, including QTc prolongation, T-wave flattening or inversion, bradycardia, sick sinus node syndrome, and AV block.

Lithium is a Human Teratogen!

Lithium is associated with cardiac malformations (in particular, Ebstein's anomaly) and increased birth weight.[24] Every woman of child‐bearing age on lithium should be advised to use a reliable form of contraception.
  • Long-term use of lithium (i.e. - over decades) has been linked to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The estimated risk of developing CKD and progressing to ESRD is around 1.5% in long-term lithium users.[25] Importantly, the majority of patients on long-term lithium treatment do not appear to develop impaired renal function.[26]
  • Routine monitoring for both creatinine and eGFR is thus important for patient on lithium. There are no strict eGFR cut-offs for discontinuing lithium if there is concern about nephrotoxicity (CKD is defined as eGFR <60mL/min). Guidelines suggest referring to nephrology if:[27]
    • eGFR falls by >5 mL/min in 1 year, or >10 mL/min within 5 years, or
    • eGFR <45mL/min in two consecutive readings, or
    • Clinician is concerned for other reasons
  • Interestingly, drinking caffeine can reduce lithium levels, as it is thought to increase renal lithium clearance.[28]
  • For geriatric patients, lithium levels should be <0.8 mmol/L where possible (0.4 to 0.6 for depression, and 0.4 to 0.8 for mania/hypomania). Once daily dosing is best, and it is best to start at a lower dose of 150 mg per day.
    • Typically, 450 mg per day is enough to reach a therapeutic level for geriatric patients. In some cases, a therapeutic effect is achieved between 0.2 to 0.6 mmol/L, this is because there is a lower correlation between serum lithium levels and cerebrospinal levels in older age (due to a leakier blood brain barrier).
  • Make sure that chronic conditions like diabetes, hypertension, and cardiovascular risk factors are well-controlled. The medical risks and benefits of lithium needs to be carefully weighted in older users of lithium, particularly when chronic kidney disease is more common in this population. Lithium overall remains an under-utilized treatment in this population despite overwhelming evidence for it use, its possible neuroprotective effects, and decreased mortality rates.
  • Lithium should be held 24 hours prior to delivery due to risks of massive fluid shifts from delivery causing lithium toxicity
  • For pregnancy women on lithium, post-delivery, it is essential to monitor the infant for signs of hypotonia and “floppy baby syndrome” in the first 48 hours.
  • Breastfeeding is also not recommended as lithium is expressed in the breast milk
  • Lithium levels and renal function should be closely monitored in those with renal disease.
2) Taylor, David. Chapter 3, Bipolar Disorders. The Maudsley Prescribing Guidelines in Psychiatry, Twelfth Edition. pg. 189
12) Taylor, David. Chapter 3, Bipolar Disorders. The Maudsley Prescribing Guidelines in Psychiatry, Twelfth Edition. pg 190.